Abstract

Objective

To evaluate the effectiveness of maintenance therapy with fluconazole, an antifungal
agent, in patients with AIDS who have completed successful primary therapy for cryptococcal
meningitis.

Design

Randomized, double-blind, placebo-controlled trial with a mean duration of 140 days
(range, 13 to 529 days).

Setting

3 university-affiliated medical centers and 1 private medical group in the United
States.

Patients

Adults with documented HIV infection who had successfully completed a standardized
course of amphotericin B therapy or amphotericin B plus flucytosine therapy (within
the past 3 weeks) for recently diagnosed cryptococcal meningitis (within the past
4 months) were included. Patients were excluded if they had a history of intolerance
to imidazoles, moderate liver function abnormalities, a serum creatinine level >
190 µmol/L; if they were pregnant; or if they were receiving systemic or intrathecal
antifungal therapy. Of 84 patients enrolled, 16 were found to be ineligible because
of silent, persistent infections. Of the 68 eligible patients randomized, 7 (10%)
were lost to follow-up.

Intervention

During phase I, patients received either 100 mg of oral fluconazole or identical placebo
for 3 months. During phase II, patients received either 200 mg of fluconazole or placebo
daily.

Main outcome measure

Recurrence of cryptococcal infection at any site.

Main results

More patients receiving placebo than those receiving fluconazole had a recurrence
of cryptococcal infection (P < 0.001) (Table). 4 of the patients receiving placebo (15%) and none of the patients
receiving fluconazole had meningeal recurrence (difference in risk 15%, CI 1% to 28%,
P = 0.03). The cumulative risk for recurrence of cryptococcal infection at any site
after 1 year was 100% in the placebo group and 5% in the fluconazole group (P < 0.001). The best predictor of recurrence-free survival was fluconazole treatment
(P = 0.02). The occurrence of adverse events was similar in the 2 treatment groups (P = 0.80), with gastrointestinal symptoms being reported most frequently.

Conclusion

Treatment with fluconazole at a dosage of 100 to 200 mg/d was effective in preventing
recurrence of cryptococcal infection at any site in patients who have completed clinically
successful standard therapy for cryptococcal meningitis.

Sources of funding: California University-Wide AIDS Research Program and Pfizer Central
Research.

Table. Fluconazole vs placebo for treating patients with AIDS who have had successful primary
therapy for cryptococcal meningitis*

Outcome at mean follow up of 140 d

Fluconazole

Placebo

RRR (95%CI)

NNT (CI)

Recurrence of cryptococcal infection

3%

37%

92% (57 to 99)

3 (2 to 6)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.

Updated Commentary

Cryptococcal meningitis was reported to occur in approximately 10% of patients with
AIDS and frequently recurs after the primary therapy for meningitis is terminated.
A collaborative trial (1) suggested that fluconazole is effective for preventing recurrent cryptococcal disease,
which the current report further documents.

The study was well planned and analyzed. The baseline characteristics of the 2 groups
were comparable except that patients on placebo received somewhat less flucytosine
and had higher cryptococcal antigen titers. These differences, however, were probably
not great enough to affect the validity of the conclusions.

Of particular importance is that none of the 34 patients on fluconazole maintenance
therapy developed recurrent meningitis, compared with a 15% recurrence rate among
patients on placebo. The mortality rates were the same for the 2 groups. However,
none of the 7 deaths in the fluconazole group, compared with 2 of the 4 deaths in
the placebo group, were attributable to cryptococcal disease.

Fluconazole, 200 mg/d, is well tolerated and should be prescribed to prevent recurrence
of cryptococcosis among patients with AIDS who have had successful initial treatment.
Although the success of highly active antiretroviral therapy has led to a reassessment
of the role of prophylactic therapies, only limited studies have evaluated the safety
of stopping secondary prophylaxis for cryptococcal infections in patients who have
had an immunologic response to antiretroviral therapy and current guidelines recommend
its continuation (2). Although fluconazole taken as primary prophylaxis reduced the frequency of fungal
infections in patients with advanced HIV infection (3), its use is not routinely recommended (2).

Author's Response

Readers should note that fluconazole prevented urinary as well as meningeal recurrence.
This is important because the early detection and treatment of persistent and recurrent
extraneural disease probably accounted for the unexpectedly low rate of meningeal
recurrence in the placebo group. Also, the fact that all meningeal recurrences occurred
between monthly visits whereas all urinary recurrences were detected at monthly visits
suggests that follow-up urine cultures for fungus may be worth while in this patient
group, but that once sterility has been achieved, routine lumbar punctures are not
needed.